Skeletal Muscle Alterations in Different Phenotypes of Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) shows diverse disease patterns, with various combinations of comorbidities and symptoms. A common hallmark is exercise intolerance, caused by alterations in the peripheral skeletal muscle (SKM) including a recently indicated titin hyperphosphorylation. Our aim is to compare a metabolic syndrome- (ZSF-1 rats) and a hypertension-driven (Dahl salt-sensitive (DSS) rats) HFpEF rat-model in relation to SKM function and titin phosphorylation. Obese ZSF-1 and high-salt fed DSS rats (HFpEF) were compared to lean ZSF-1 and low-salt fed rats (con). HFpEF was confirmed by echocardiography and invasive haemodynamic measurements. SKM atrophy, in vitro force measurements, titin- and contractile protein expression were evaluated. Obese ZSF-1 HFpEF rats showed muscle atrophy, reduced muscle force and increased titin phosphorylation compared to controls, which was not detected in hypertensive DSS rats. Fiber type specific troponins, myostatin and four and a half LIM domain 1 were differently regulated between the two models. Altogether, our results show that both animal models of HFpEF exhibit different SKM phenotypes, probably based on the divergent disease etiologies, which may help to define the most suitable animal model for HFpEF to test potential treatment regimens.